Process for converting a type prostaglandins to E type prostaglandins

ABSTRACT

A process for the conversion of A type prostaglandins to E type prostaglandins is disclosed. Heretofore unknown prostaglandin derivatives are utilized as intermediates in the process.

United States Patent [191 Leeming et al.

[ Oct. 14, 1975 PROCESS FOR CONVERTING A TYPE PROSTAGLANDINS TO E TYPEPROSTAGLANDINS [75] Inventors: Michael R. G. Leeming, Canterbury,

England; Donald P. Strike, St. Davids; Wen-Ling Kao, Devon, both of Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: June 5, 1974 [21] Appl. No.: 476,757

Related US. Application Data [62] Division of Ser. No. 284,789, Aug. 30,1972, Pat. No.

[52] US. Cl 260/240 R; 260/3457; 260/345.8; 260/468 D; 260/514 D;260/999 [51] Int. Cl. C07D 309/06; CO7D 309/22; C07C 69/02 [58] Field ofSearch 260/240 R, 468 D, 514 D, 260/3457, 345.8

Primary Examiner-Arthur P. Demers Attorney, Agent, or FirmRobert Wiser[57] ABSTRACT A process for the conversion of A type prostaglandins to Etype prostaglandins is disclosed. Heretofore unknown prostaglandinderivatives are utilized as intermediates in the process.

3 Claims, No Drawings PROCESS FOR CONVERTING A TYPE PROSTAGLANDINS TO ETYPE PROSTAGLANDINS CROSS-REFERENCE TO RELATED APPLICATION Thisapplication is a divisional of US. pat. application Ser. No. 284,789,filed Aug. 30, 1972, now US. Pat. No. 3,839,430.

BACKGROUND OF THE INVENTION The prostaglandins are a group of chemicalcompounds, whose members possess a broad spectrum of pharmacologicactivities. The E type prostaglandins, which contain the substitutedcyclopentano moiety are particularly important as they have beengenerally shown to be the most pharmacologically active class ofprostaglandins. E type prostaglandins have been obtained mainly byextraction of mammalian tissue, in which they occur in very smallamounts. The source, method of collection, and their inherentinstability combine to make collection of E type prostaglandins fromnatural sources, a tedious and inefficient means of obtaining thesevaluable and important compounds.

Recently, total and partial syntheses of E type prostaglandins have beenreported. A partial synthesis beginning with the A type prostaglandins,ie those possessing the substituted cyclopentano moiety [G. L. Bundy, W.P, Schneider, F. Lincoln, and J.

E. Pike, J. .Am. Chem. Soc., 94, 2123 (1972)] has become particularlyimportant since the discovery A. J weinheimer, and R. L. Spraggins,Tetrahedron Letters, 59 1969)] that 15 epimeric A type prostaglandinsmay be collected in substantial quantities from the coral Plexaurahomomalla (Esper), a non-mammalian source. The epimerigationwhich isrequired to convert the IS-epimeric A type prostaglandins obtained fromPlexaura homomalla (Esper), to the configuration of the prostaglandinsfound in mammalian tissue is described in the copending US. applicationof Donald P. Strike and Herchel Smith; Ser. No. 223,722, filed Feb. 4,1972, now abandoned.

It is the primary object of the present invention, to provide processeswhereby A type prostaglandins may conveniently be converted to E typeprostaglandins.

It is the secondary object of the present invention to provide,heretofor unknown, valuable, intermediates for the synthesis of E typeprostaglandins.

SUMMARY OF THE INVENTION The invention sought to be patented in aprincipal process aspect resides in the concept of a process forpreparing a compound of the formula in which R ishydrogen or alkyl offrom I m about 6 carbon atoms, R is hydrogen, Z-tetrahydropyranyl, orcarboxylic acyl of from 1 to about 6 carbon atoms, and

i. X, Y and Z are single bonds; ii. X is' a trans-double bond, Y and Zare single bonds; iii. X is a trans-double bond, Y is a cis-double bond,

Z is a single bond; or iv. X is a trans-double bond, Y and Z arecis-double bonds; comprising:

a. treating a compound of the formula [,W OR

in which R, R, X, Y, and Z are as defined above with an epoxidizingagent to form a compound of the formula,

b. treating the thus formed epoxide with hydrogen bromide to formacompound of the formula and c. treating the thus formed bromohydrinwith tri-nbutyltin hydride. The invention sought to be patented in asecond process aspect resides in the concept of a process for preparinga compound of the formula in which R is hydrogen or alkyl of from l toabout 6 carbon atoms, and I i i. X, Y and Z are single bonds;

ii. X is a trans-double bond, Y; and Z are single bonds;

iii. X is a trans-double bond, Y is a cis-doublebond Z is a single bond;or 7 iv. X is a trans-double bond, Y and Z are cis-double bonds;comprising:

a. treating a compound of the formula in which R, X, Y, and Z are asdefined above with an epoxidizing agent to form a compound of theformula b. treating the thus formed epoxide with hydrogenbromide to forma compound of the formula c. treating the thus formed bromohydrin withdilute acid .to form a compound of the formula and d. treating the thusformed bromohydrin with tri-nbutyltin hydride. The invention sought tobe patented in a principal composition aspect resides in the concept ofa compound of the formula in which R is hydrogen or alkyl of from 1 .toabout 6 carbon atoms, R is hydrogen, Z-tetrahydropyranyl, or carboxylicacylof from 1 to about-6 carbon atoms. and

i. X, Y and Z are single bonds;

ii. X is a trans-double bond, and Z are single bonds;

iii. X is a trans-double bond, Y is a cis-double bond,

Z is a single bond; or a iv. X is a trans-double bond, Y and Z arecis-double bonds. l

The tangible embodiments of the principal composition aspect of theinvention possess the inherent physical properties of being generallycolorless to light yellow colored oils, are substantially insoluble inwater, and are generally soluble in such organic solvents as benzene,ethyl acetate, ethyl ether, and methanol. EX- amination of the compoundsproduced according to the hereinafter described process reveals, uponinfrared. ultraviolet mass, and other nuclear magnetic resonancespectrographic analysis, spectral data supporting the molecularstructurehereinbefore set forth. For example, the bromine function is evident inthe mass spectrum while the epoxide function is evident from the nuclearmagnetic resonance spectrum. The'aforementioned physical characteristicstaken together with the nature of the starting materials confirm themolecular structure as hereinbefore set forth.

The tangible embodiments of the principal composition aspect of theinvention possess the applied use characteristic of being intermediatesfor making compositions which possess the inherent applied usecharacteristic of exerting qualitatively varying effects in animals asevidenced by pharmacologicalevaluation according to standard testprocedures, particularly, as bronchodilators, hypotensive agents, agentsfor reduction of gastric secretion, andagents for inhibition of bloodcell adhesiveness.

The invention sought to be patented in a second composition aspectresides in the concept of the compound of formula The tangibleembodiment of the second composition aspect of the invention possessesthe inherent physical properties of being a colorless oil, issubstantially insoluble in water. and soluble in such organic solventsas 5 benzene. ethyl acetate, ethyl ether, and methanol. Examination ofthe compound reveals. upon infrared, ultraviolet, mass, and nuclearmagnetic resonance spectrographic analysis. spectral data supporting themolecular structure hereinbefore set forth.

O l0 C0 H I l r l Iva OH IVb 0H DESCRIPTION OF THE INVENTION actionsequence for converting a specific A type pros- I taglandin to an E typeprostaglandin. Those skilled in the art will recognize that in thestructures the dotted lines and the heavy lines are meant to indicate,respectively, bonds directed below and abovethe plane of the page.

The A type prostaglandin molecule I which may be prepared by treatingprostaglandin A with dihydropyran and an acid catalyst (e.g.p-toluenesulfonic acid) is treated with an epoxidizing agent to form amixture of the epoxides Ila and llb. Any of the hydroperoxideepoxidizing agents known in the art may be utilized for this purpose,e.g. hydrogen peroxide, nbutylhydroperoxide and the like; thosepreferred are basic hydrogen peroxide in alkanol solution, and basicn-butylhydroperoxide. The epoxidation may be carried out under a varietyof reaction conditions and in a variety of solvents. The preferredsolvents are aqueous alkanol mixtures (i.e. methanol-water;.ethanol-water) while the preferred temperature range is from about 40to about +l for times of from about 15 minutes to about 5 hours. Thoseskilled in the art of organic chemistry will recognize that a mixture oftwo isomeric epoxides Ila and llb are formed as a result of thisreaction. The epoxide mixture is next treated with hydrobromic acid toproduce the mixture of bromohydrins Illa and Illb. The hydrogen bromideaddition to the epoxide molecules proceeds particularly efficiently whenone utilizes a mixture of acetic acid and diethyl ether as solvents attemperatures of from about to +1 0 for periods of time varying fromabout 10 minutes to about 1 hour. If desired, variation of the solventsand reaction conditions will suggest themselves to those skilled in theart of organic chemistry, these parameters not being critical. Themixture of bromohydrin molecules Illa and lIIb is next treated withdilute acid, for example I N hydrochloric acid, to remove the 2-tetrahydropyranyl group, thus producing bromohydrin compounds IVa andlVb. It will be obvious to those skilled in,the art that if the2-tetrahydropyranyl group is replaced with a carboxylic acyl group, forexample, ethanoyl or butanoyl, that such a group may be re moved byeither dilute acid or dilute base hydrolysis (preferably dilute basichydrolysis). The compounds IVa and IVb are next treated withtri-n-butyltin hydride and azobisisobutyronitrile preferably in benzeneat 70, to remove the bromine atom, and the mixture of prostaglandin Emolecules Va and Vb so produced may be isolated and purified by variousof the means known in the art such as chromatography. If .desired, the2- tetrahydropyranyl group need not be removed, prior to the removal ofthe bromine atom.

It is well-known in the art of organic chemistry, that two isomericepoxides may be produced on epoxidation of an unsymmetricallysubstituted double bond. The ratio of the two resultant isomericepoxides need not of necessity be equal to unity, and indeed, it is welldocumented in the organic chemical literature that, for example, stericanc electronic factors inherent in the molecule or the reactionconditions, may cause one of the isomers to predominate. Thus, treatmentof the epoxide mixture Ila and 11b, when produced by epoxidation of theA type prostaglandin I with n-butylhydroperoxide in basic methanolsolution, with hydrobormic acid produces the bromohydrin molecules Illaand lllb in a ratio of 1:4. One skilled in the art of organic chemistrywill recognize that epoxide llb will yield bromohydrin [11b and lla willlikewise yield llla when treated with hydrobromic acid, thus the ratioof bromohydrins produced can be corrolated with the ratio of the epoxideisomers in the mixture. This observation has proven fortuitous, sincethe bromohydrin lllb ultimately yields the prostaglandin E (Vb), thusproviding an efficient and practical means for converting prostaglandinA into the valuable prostaglandin E The preparation of increased amountsof the II- epimeric isomer .has also been accomplished. Thus epoxidationof prostaglandin A with basic hydrogen .peroxide in methanolic solutionfollowed by treatment of the epoxide mixture with hydrobromic acid hasbeen shown to produce the bromohydrins [Va and lVb in 1:1 ratio. Whileepoxidation of prostaglandin A with basic n-butylhydroperoxide followedby treatment of the epoxide mixture with hydrobromic acid produces thebromohydrins [Va and IVb in a ratio of 2:3.

Again referring to FIG. 1, it will be obvious to those skilled in theart, that the epoxide mixture may be separated for example bychromatography prior to treatment with hydrobromic acid, thus permittingthe preparation of the isomerically pure bromohydrin molecules Illa andIIlb. Alternately, the bromohydrin mixture Illa and lllb may be preparedfrom the mixture of epoxides and then separated, for example bychromatography. Further, the mixture of bromohydrin molecules Illa andlIlb may first be hydrolyzed to remove the 2-tetrahydropyranyl groupproducing bromohydrins IVa and IVb which mixture may be separated, forexample, by chromatography prior to the removal of the bromine atom or,the bromine atom may be removed without separating lVa from IVb, and theresulting mixture of prostaglandin E molecules may be separated forexample by chromatography.

In the preferred reaction sequence, the A type prostaglandin I isepoxidized with n-butylhydroperoxide the isomer mixture Ila and llb istreated with hydrobromic acid, yielding the mixture of bromohydrinmolecules Illa and Illb which mixture is hydrolyzed with dilutehydrochloric acid solution to remove the 2- tetrahydropyranyl groupproducing the isomer mixture IVa and IVb which mixture is separatedchromatographically yielding a ratio of IVa to IVb of 1:4. The pureisomers IVa and IVb are then treated separately withtri-n-butyltinhydride to produce the isomerically pure E prostaglandins Va and Vb.While the process of theinvention has been described with reference to aspecific embodiment thereof, it will be apparent to those skilled in theart that 'it will work equally well for all embodiments within the scopeof the invention.

In the following examples, the upper case letters S and R used in namingthe compounds produced refer respectively to the natural and epimericstereo form about the 3 position of the 8 carbon chain (U.S. von Euler,and R. Eliasson, Prostaglandins page 16, 1967 Academic Press, N. Y.).Thus the structure in FIG. 1 all display the natural or S configurationabout this center.

EXAMPLE 1 7 -[2-(3-S-[Tetrahydropyran-Z-Yloxy]-1-Octenyl )-5- Oxo- 3-Cyclopenten-1-yl ]-5-Heptenoic Acid (I) EXAMPLE 2 7-[4aBromo-3B-Hydr0xy-2-(3 S-Hydroxy-1-Octenyl)-5-Oxocyclopentyl]-5-Heptenoic Acid (IVa) and7-[4B-Bromd-3a-Hydroxy-2-(3-S Hydroxy-l-Octenyl)'5-OxocyclopentylJ-S-Heptenoic Acid (lVb) A solution of 1.14 g.of 7-(2-[3-S-(tetrahydropyran-2-yloxy)-l-octenyl]-5-oxo-3-cyclopenten-1-yl)-5- heptenoic acid in 17ml. of methanol and 1.1 ml. of water was mixed at 25 to 30C. with 4.98g. of nbutylhydroperoxide. To this mixture, 3.15. ml. of 1N- sodiumhydroxide was added to adjust the pH to 89. After 4 hours, the reactionmixture was diluted with 20 ml. of water, acidified withacetic acid andextracted with ether. After washing with brine, drying with magnesiumsulfate the extract was evaporated to give 1.10 g. of crude oily7-[2-(3-S-[tetrahydropyran-2 yloxy]-1- octenyl]-4-oxo-6-oxabicyclo[3.1,0]hex-3-yl]-5 heptenoic acid.

A solution of the above crude product in 35 ml. of ether was treated atC. with 0.84 g. of 30% hydrogen bromideacetic acid in 8 ml. of ether andstirred for 10 minutes. The reaction mixture was diluted with 300 ml. ofether, washed, dried and evaporated to give 1.38 g. of crude oily7-(4-bromo-.3-hydroxy-2-[3-S- (tetrahydropyran-2 yloxy )-'l-octenyl]--oxocyclopentyl)-5-heptenoic acid.

A solutionof the above oily product in' 70 ml. of tetrahydrofuran wastreatedat C. with 70 ml. of 1N hydrochloric acid 'andstirre'd for 45minutes. The reaction mixture was diluted with 500 ml. of ether, washed,dried, evaporated and the residue chromatographed on silica. Elutionwith 40% ethyl acetate-hexane gave 0.10 g. t of 7-[4a-bromo-3B-hydroxy-2-(3-S-hydroxy-1- octenyl)-5-oxocyclopentyl]-5-heptenoic acidand further elution with 50% ethyl acetate hexane obtained 0.38 g. of7-[4B-bromo-3a-hydroxy-2-(3-S-hydroxy-loctenyl)-5-oxocyclopentyl1-5-heptenoicacid.

Ratio of [Va/[Yb F 1:4.

' EXAMPLE 3 7-[3a-Hydroxy-2-(3-S Hydroxy-1-Octenyl)-5- Oxocyclopentyl]5-Heptenoic Acid (Vb) A solution of 1.27 g. .of7-[4B-bromo-3a-hydroxy-2- (B-S-hydroxyl -oc te nyl-'5-oxocyclopentyl]-5- heptenoic acid and 2.04 ml. of tri-n-butyltin hydride in 200 ml. ofbenzene was-stirred at 75C. under nitrogen and treated dropwise with a,s olution v of 108g. of ambisisobutyronitrile in 50 ml. of benzeneduring 35 minutes. The mixture was stirred at C. for 15 minutes,evaporated under vacuum and the residue dissolved in ether. The ethersolution was extracted three times with 0.2M sodium phosphate buffer (pH8.5) followed by five times with 5% sodium bicarbonate and the extractsacidified to pH with hydrochloric acid and extracted with ether. Afterwashing and drying, the extract was evaporated and the residuechromatographed on silica. Elution with 70% ethyl acetate in hexanefollowed by crystallization from ethyl acetatepentane afforded 140 mg.of 7-[3a-hydroxy-2-(3-S-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid, m.p. 67-68C., mixed m.p.with PGE 66.567.5C., A 2.9, 3.0, 3.45, 5.75, 5.85, 7.6, 7.95, 8.35,8.65, 9.35, 10.0,10.35, 11.14,13.35 ;1.. NMR: 8 6.23 (3, S, OH), 5.70(2, M, C-13 and 14 H), 5.45 (2, M, C-5 and 6 H), 4.0-4.4 (2, M, C-11 and15 H) ppm. Optical rotation: [041 64.8 (c 1.0, THF [reported 61 in J.Am. Chem. Soc. 92, 397 (1970)]. Mass spectrum: M -H O at m/e 334 (theory334).

EXAMPLE 4 7-[3B-Hydroxy-2-( 3-S-Hydroxy-1-Octenyl)-5-Oxocyclopentyl]-5-Heptenoic Acid (Va) A solution of 2.8 g. of a mixtureof 7-[4a and 4B- bromo-3B and 3a-hydroxy-2-(3-S-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid and 4.48 ml. of trin-butyltin hydridein 400 ml. of benzene was stirred at 70C. under'nitrogen and treatedwith a solution of 2.4 g. of azobisisobutyronitrile in 100 ml. ofbenzene in portions over minutes. The reaction mixture was concentratedunder vacuum, diluted with ether and extracted 6 times with 5% sodiumbicarbonate solution. After acidification with acetic acid, the aqueoussolutions were extracted with ether and the extract washed, dried andevaporated. Silica chromatography of the residue with 60% ethyl acetatein hexane gave 0.23 g. of 7-[3B-hydroxy-2-(3-S-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid an oil, )t,,,,,,!"' 3.0, 3.5, 6.85,7.2, 8.2, 8.65, 10.3 p NMR: 8 6.18 (3, S, OH), 5.80 (2, M, C-13 and 14H), 5.43 (2, M C-5 and 6 H), 4.45 (l, M, C-ll H), 4.18 (1, M, C-15 PPm.Mass spectrum: M -H O at m/e 334 (theo 334). Further elution of thecolumn with 70% ethyl acetate in hexane yields7[3a-hydroxy-2-(3-S-hydroxy-1- octenyl)-5-oxo-cyclopentyl]-5-heptenoicacid. A

' EXAMPLE 5 7-[2-(3-S-Hydroxy-1-Octenyl)-4-Oxo-6- Oxabicyclo[3. 1.0]Hex-3-Yl]-5-Heptenoic Acid (Mixture of PGA a, and B Epoxides) Anice-cooled solution of 1.9 g. of 7-[2-(3-S- hydroxyl -octenyl)-5-oxo-3-cyclopenten-l -yl ]-5- heptenoic acid and 6.0 ml. of 30%hydrogen peroxide in 60 ml. of methanol and 6.0 ml. of water was treatedwith 6.6 ml. of 1 N sodium hydroxide. After stirring at 0 for 4 hour,the mixture was diluted with water, acidified with acetic acid andextracted with ether. After washing and drying,the extract wasevaporated to obtain 2.0 g. of 7-[2-(3-S-hydroxy-1-octenyl)-4-oxo-6-Oxabicyclo[3.].0]hex-3-yl]-5-heptenoic acid as an oil, h 3.05, 3.45,5.8, 7.2, 8.15, 10.3 p.. NMR: 8 6.4 (OH); 5.8(2, M, C-l3 and 14 H), 5.33(2, M C-5 and 6 H), 4.23 (1, M, C-15 H), 3.85 and 3.5 (1, M, epoxide Hs)ppm. Mass spectrum (purified sample): M -H O at m/e 332.2010 (theory332.1986). 7

EXAMPLE 6 5-Oxocyclopentyl]-5-Heptenoic Acid (IVa) and I7-[4B-Bromo-3wHydroxy-24 3-S-Hydroxy- 1Octenyl)-5-Oxocyclopenty1]-5-Heptenoic Acid (lVb) A solution of 1.9 g.of 7-[2-(3-S-hydroxy-l-octenyl)- 4-oxo-6-oxabicyclo[3.1.0]hex-3-yl]5-heptenoic acid (as prepared in Example 5) in 50 ml. of ether wascooled in a methanol-ice bath and treated dropwise with a solution of1.37 g. of 32% hydrobromicacidacetic acid in 35 ml. of ether over Ahour. After stirring at for 20 minutes,'the reaction mixture was dilutedwith ether, washed with water, dried and evaporated. Silicachromatography, of the resulting product mixture with 40% ethyl acetatein hexane gave 0.73 g. of7-[4a-bromo-3B-hydroxy-2-(3-S-hydroxy-1-octenyl)-oxocyclopentyl]-5-heptenoic acid as an oil, A 3.0, 3.4, 5.7, 5.85, 7.1,8.2, 9.5, 10.25 ;L. NMR: 8 5.98 (3, OH), 5.73 (2, M, 01314 H), 5.4 (2,M, C- 5 and 6 H), 4.0-4.44 (3, M, C-10, 11 and 15 H) PPm. Mass spectrum: M 2H O at m/e 394 (theory 394). 1

Further elution with 50% ethyl acetate in hexane afforded 0.67 g. of7-[4,B-bromo-3a-hydroxy-2-(3-S-hydroxy-1octenyl)-5-oxocyclopentyl]-5-heptenoic acid as an oil, )t 3.0,4.4, 5.7, 5.85, 7.1, 8.7 10.3 a. NMR: 5 6.1 (3, OH), 5.65 (2, M, C-13and 14 H), 5.43 (2, M, C-5 and 6 H), 3.9-4.4 (3, M, C-10, 11 and 15 H)ppm. Mass spectrum: M 2H O at m/e 394 (theory 394).

Ratio of IVa/IVb 1:1.

EXAMPLE 7 and 7-[4l3-Bromo-3a-Hydroxy-2-( 3-S-HydroxylOctenyl)-5-Oxocyclopentyl]-5-Heptenoic Acid (IV b) A solution of 0.50 g.of 7-[2-(3-S-hydroxy-1- octenyl)-5-oxo-3-cyclopenten-1-yl]-5-heptenoicacid in 9 ml. of methanol and 0.5 ml. of water was mixed at 25 to 30C.with 2.70 g. of n-butylhydroperoxide. To this mixture, 1.75 ml. of 1 Nsodium hydroxide was added to adjust the pH to 8-9. After 4 hours, thereaction mixture was diluted with 10 ml. of water, acidified with aceticacid and extracted with'ether. After washing with brine, drying overmagnesium sulfate, the extract was evaporated to give 0.48 g. of crudeoily 7-[2- (3-S-hydroxy-1-octenyl)-4-oxo-6- oxabicyclo[ 3. l .0]hex-3-yl]-5-heptenoic acid.

A solution of the above crude product in 20 ml. of ether was treated at0C. with 0.60 g. of 30% hydrogenbromideacetic acid in 5 m1. of ether andstirred for 10 minutes. The reaction mixture was diluted with 200 ml. ofether, washed, dried evaporated and the residue chromatographed onsilica. Elution with40% ethyl acetate-hexane gave 0.19 g. of7-[4a-bromo-3B-hydroxy- Ratio of lVa/lVb 2:3.

EXAMPLE'8 7-[2-(3-R-Hydroxy-l-Octenyl)-4-Oxo-6- 5Oxabicyclo[3.1.0]Hex-3-Ylj-5-Heptenoic Acid (Mixture of -epi-PGA', a,and B Epoxides) A solution of 0.95 g. of l5-epi-PGA and 2.5 ml. of 30%hydrogenperoxide in 25 ml. of methanol and 2.5 ml. of water was cooledto5C. in amethanol-ice bath andtreated with 3.0 ml. of 1 N" sodiumhydroxide in portions over 2.5hours. The reaction mixture was dilutedwith water, acidified with acetic acid and extracted with ether. Afterwashing and drying, the extract was evaporated and the residuechromatographed on silica. Elution with 40%.ethyl acetate in hexaneafforded 0.38 g. of 7-[2-(3-R-hydroxy-1-octenyl)-4-oxo-6-oxabicyclol3l1.0]hex-3-yll 5-heptenoic acid as an oil, )t f 3.0(shoulder), 3.45, 5.8, 7.1, 10.3, 11.9 a. NMR: 8 6.68 (3, S, OH), 5.63(2, M, C-13 and 14 H), 5.43 (2, M, C-Sand 6 H), 4.13 (1, M, C-15), 3.78and 3.48 (1, d, J= 2.3, epoxide Hs) ppm. Mass spectrum: M at m/e'350(theory 350) M H O at m/e 332.1979 (theory 332.1986).

The subject matter which the applicants regard as their invention isparticularly pointed out and distinctly claimed as follows:

A compound of the formula:

in which R is hydrogen or alkyl of from 1 to about 6 carbon atoms, R is2-tetrahydropyranyl, orcarboxylic.

acyl of from 1 to 6carbon atoms, and i. .X,.Y and Z aresingle bonds; ii.X is a trans-double bond, Y and Z are single bonds; iii. X is atrans-double. bond; Y is a cis-double bond,

2 is a single bond; or

iv. X is a trans-double bond, Y and Z are cis-doublebonds; with theproviso that the bromine and hydroxy ring substituents be.in a transstereochemical configuration.

2. The compound of claim l which so isi 6 3.'The compounds of claim l inwhich X is a trans-double bond Y is a cis-double bond Z is a singlebond.

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 which is:
 3. The compounds of claim 1 in which X is a trans-double bond Y is a cis-double bond Z is a single bond. 